tbuckley/cabot-search huggingface dataset:
Weight loss in chronic obstructive pulmonary disease
Authors: MF Muers, JH Green
Journal: European Respiratory Journal (1993)

Weight loss occurs in about a third or more disabled patients with chronic obstructive pulmonary disease (COPD), and appears to be a poor prognostic factor. As such, it correlates only weakly with FEV1, transfer factor and other measures of respiratory physiology and is probably, to a certain extent, independent of them. Recent studies of basal metabolic rate (BMR) in COPD using steady-state, non-invasive calorimetry, have shown it to be elevated by 10-20% in up to 40% of such patients. It is likely that this represents true hypermetabolism per kilogram of fat free mass. An elevated BMR cannot be predicted from combinations of detailed lung function tests or arterial gases, as patients with similar physiology have differing BMRs. Thus, although an increased work of breathing is the probable explanation for some of the increase, other factors such as cytokines or possibly drug therapy almost certainly contribute. Muscle loss in weight-losing COPD appears to involve both type I and type II fibres, because of a combination of reduced calorie intake and disuse atrophy. Respiratory muscles share this fibre loss. Review of the controlled studies on nutritional supplementation in COPD suggests that an energy increase of about 30% is needed to achieve substantial weight gain and improve exercise tolerance. Fat-rich supplements have some theoretical advantages. Further work is needed particularly with regard to the determinants of the increased BMR in COPD, and the effect of longer term nutritional supplements on prognosis.
Abstract P3048: Establishing The Mitochondrial Citrate Transporter As A Regulator Of Cardiac Development
Authors: Nasab Ghazal, Jessica N Peoples, Allie A Rodgers, Austin S Park, Jennifer Q Kwong
Journal: Circulation Research (2022)

Introduction: Mitochondria are essential to provide oxidative energy to fuel excitation-contraction coupling of the postnatal heart. The role of mitochondrial energy production systems in the hypoxic environment of the embryonic heart is less clear, but defects in mitochondrial energy production machinery are associated with ventricular wall defects such as left ventricular noncompaction. In developing models to study mitochondrial function specifically in the postnatal mouse heart, we uncovered an unexpected embryonic-lethal knockout model that suggested roles for mitochondrial function in heart development. Uncovering mechanisms connecting mitochondrial function to the tightly regulated process of ventricular wall morphogenesis could reveal novel roles for mitochondria during development and guide further studies of developmental heart defects. Hypothesis: The mitochondrial citrate carrier (SLC25A1), a mitochondrial inner membrane transporter implicated in regulating mitochondrial function in neurons, is essential for ventricular wall morphogenesis and cardiac development. Methods and Results: We investigated the role of the mitochondrial citrate carrier (SLC25A1) in cardiac development. Slc25a1 knockout mice display impaired growth and do not survive past embryonic day (E) 18.5. Hearts from E18.5 Slc25a1 knockout embryos display a striking array of cardiac malformations including persistence of an expanded zone of trabeculated myocardium, reduced compact myocardium, and ventricular septal defects. Analysis of mitochondrial structure and function revealed that loss of Slc25a1 causes mitochondrial ultrastructural defects and depressed mitochondrial respiration. Conclusions: Our results highlight a novel role for SLC25A1 in cardiac development with specific roles in regulating both ventricular wall development and mitochondrial energetics during heart morphogenesis. Ongoing work will identify the mechanisms by which SLC25A1—a mitochondrial transporter that is not a primary component of the mitochondrial oxidative phosphorylation system—regulates mitochondrial energetics, which will help us delineate new pathways connecting mitochondria to heart development.
Phase II study of trastuzumab-pkrb and docetaxel anhydrous combination therapy in recurrent or metastatic salivary ductal carcinomas (KCSG HN18-08/KM11).
Authors: Jiyun Lee, Sehhoon Park, Hyun Ae Jung, Se-Hoon Lee, Seyoung Seo, Sung-Bae Kim, Ji-Won Kim, Keun Wook Lee, Eun Joo Kang, Ju Won Kim, Yoon Ji Choi, Byoung Yong Shim, Ho Jung An, Lee Chun Park, SeongHoon Shin, Jae-Joon Kim, So Yeon Oh, Min Kyoung Kim, Myung-Ju Ahn
Journal: Journal of Clinical Oncology (2022)

6018 Background: Salivary gland cancers (SGCs) are relatively rare, accounting for 1-6% of all neoplasms of the head and neck, have diverse disease course with respect to origin and pathology. Salivary duct carcinoma (SDC) is the most aggressive tumor subtype of primary SGC, showing high rates of local recurrence and distant metastases. In regard to previous studies which reported a high prevalence of HER2 positivity in SDCs, we conducted a single-arm, phase II study to evaluate the antitumor activity and safety of Herzuma (a trastuzumab biosimilar which demonstrated an equivalent efficacy to reference trastuzumab) in combination with docetaxel anhydrous (Nanoxel) in patients with HER2-positive advanced SDCs. Methods: Eligible patients had histologically confirmed HER2-positive (defined as IHC≥2+ and/or FISH HER2/CEN17 ratio ≥2.0) recurrent/metastatic SDC, or subtypes of SGC that were pathologically similar to SDC (excluding ACCs). They received Herzuma (8mg/kg i.v. loading dose, followed by 6mg/kg i.v.) and Nanoxel (75mg/m2 i.v.) every 3 weeks. The primary endpoint was the investigator-assessed objective response rate (ORR) according to RECIST v1.1. Secondary endpoints were overall survival (OS), progression-free survival (PFS), and safety. The calculated sample size was 43 patients for H1 of ORR ≥40%. Safety was evaluated by CTCAE v4.0. Results: A total of 43 patients were enrolled. Patient characteristics included: median age 60 (range 35–81); 86% male; 84% ECOG1; 84% SDC, 9% adenocarcinoma, 2% high grade mucoepidermoid carcinoma, and 5% other subtypes. Confirmed ORR was seen in 67% (95% CI, 52–81). No patient had a complete response as their BOR, 29 (67%) had a partial response, 11 (26%) had stable disease, 1 (2%) had progressive disease, and 2 (5%) were unevaluable. The DCR was 93% (95% CI, 81–99). The median PFS and OS were 8.2 months (95% CI, 6.7–9.7) and 23.3 months (95% CI, 19.9–26.7), respectively. Thirty-eight (88%) patients experienced a treatment-related AE (TRAE), with 15 (35%) patients experiencing ≥grade 3 TRAE including: neutropenia (10), febrile neutropenia (4), anemia (1), sepsis (1), anaphylaxis (1), decreased LVEF (1). There were no treatment-related deaths. Conclusions: The study met the primary endpoint of ORR. Herzuma and Nanoxel combination therapy demonstrated a promising treatment outcome in patients with HER2-positive recurrent/metastatic SDC. Clinical trial information: NCT03614364.
Abstract P1045: Targeting The EF-hand Containing Domain 1 Protein (EFHD1) In Cardiac Disease
Authors: David R Eberhardt, Xue Yin, Anthony Balynas, Sandra Lee, Maureen Walsh, Corbin Andrea, Katsuhiko Funai, Frank Sachse, Dipayan Chaudhuri
Journal: Circulation Research (2022)

Mitochondrial dysfunction due to calcium overload is common in heart disease and results in heart failure. In a mouse model of mitochondrial cardiomyopathies we noted a substantial downregulation of the gene encoding for the EF hand containing domain 1 protein (EFHD1). EFHD1 is a mitochondrial protein which binds calcium and has been shown to stimulate both apoptosis and mitoflashes. These processes involve mitochondrial calcium overload. We hypothesized that EFHD1 down regulation could represent a natural response by failing hearts to prevent mitochondrial calcium overload by increasing the calcium handling of mitochondria. We therefore studied the calcium handling properties of mice where EFHD1 had been knocked out using CRISPR Cas9. These mice are viable and we have found no adverse cardiac or metabolic phenotypes. We find that EFHD1 is expressed in the intermembrane space of the mitochondria and associates strongly with endoplasmic reticulum (ER)-associated mitochondrial membranes. Mitochondria isolated from Efhd1 knockout mice also exhibited a &amp;lt;250±10 % improvement in calcium retention in liver and neonatal mouse hearts were 3 times more resistant to hypoxia. Further, Efhd1-/- cardiomyocytes exhibit reduced ROS and mitoflash events at both baseline and following ischemia-reperfusion. These findings suggest that EFHD1 participates in ER-mitochondrial calcium exchange and that EFHD1 ablation is cardioprotective during ischemia-reperfusion.
Abstract P3111: Can ACE Inhibitors Provide Similar Long-lasting Cardioprotection Against Chronic Anthracycline Cardiotoxicity As An Approved Drug Dexrazoxane On A Well-established Animal Model?
Authors: Martin Sterba, Zuzana Pokorna, Petra Kollarova, Olga Lencova, Jan Kubes, Yvona Mazurova, Michaela Adamcova, Tomas Simunek
Journal: Circulation Research (2022)

Background: ACE inhibitors (ACEi) have been reported cardioprotective in a secondary prevention of anthracycline (ANT) cardiotoxicity in high-risk patients. However, it remains to be determined whether they can also prevent the onset of ANT-induced cardiac damage and provide long-lasting cardioprotection in primary settings similarly as approved drug dexrazoxane (DEX). Objectives: The aim of this study was to assess whether ACEis can prevent TOP2B-mediated DNA damage induced by ANTs in the heart as a very upstream event, and thus provide long-lasting cardioprotection against chronic ANT cardiotoxicity. Methods: Chronic cardiotoxicity was induced in rabbits by daunorubicin (DAU, 3 mg/kg weekly for 10 weeks). Perindopril (PER) in two clinically relevant doses (0.05 and 0.1 mg/kg/day) was administered before and throughout the chronic DAU treatment. The cardioprotection was evaluated at the end of treatment period and after 3- and 10-week drug-free post-treatment follow-up (FU). TOP2B-depedent DNA damage signaling in the heart was determined 6 h after single dose of DAU, while TOPB interaction was studied in vitro ; the results were compared to DEX. Results: A week after completion of the chronic DAU administration, PER-co-treatment completely overcame or markedly reduced DAU-induced mortality, blood congestion and systolic dysfunction (LVFS 41.5% vs. 34.3% in the DAU group, p&lt;0.05), increase of troponin T in plasma and histopathological changes in the heart. However, most of these parameters were significantly deteriorated during 3-week drug-free FU. Further worsening of the left ventricular systolic function and cardiac morphological damage occurred in the 10-week FU which led to a heart failure-related mortality in the PER co-treated group. DEX showed very effective protection against DAU cardiotoxicity both at the end of chronic treatment and after the 10-week FU. In contrast to DEX, the PER co-treatment did not affect TOP2B activity in vitro and did not prevent DAU-induced acute p53-mediated DNA damage signaling in the heart. Conclusions: Unlike approved drug DEX, the ACEi treatment provided only temporary control of ANT cardiotoxicity development which may be associated with the lack of the effects on ANT-induced and TOP2B-mediated DNA damage response in the heart.
Abstract P3097: Post-transcriptional Mechanisms Of FTO-regulated Cardiac Contractility
Authors: Mihir Parikh, Anh Phan, Prabhu Mathiyalagan, Susmita Sahoo
Journal: Circulation Research (2022)

Background: N6-methyladenosine (m6A), the most abundant and functionally relevant mRNA modification, is reversibly demethylated by FTO, an m6A eraser and a primary regulator of m6A in the heart. In failing hearts, decreased FTO increases m6A, critically reducing cardiomyocyte contraction. FTO overexpression improved cardiac contraction and attenuated remodeling. Here, we investigate post-transcriptional and translational mechanisms of FTO-regulation of cardiomyocyte contraction in vitro and in vivo. We hypothesize that FTO directly binds to selective cardiac contractile mRNAs at their m6A site and affects their nuclear export, polysome binding, cytoplasmic availability, and protein expression. Methods and Results: We performed immunostaining to examine the intracellular location and expression of FTO under different pathological stimuli in human ventricular cardiomyocyte cell line (AC16 cells), rat primary cardiomyocytes and mouse and human hearts. FTO was detected in both cytoplasmic and nuclear compartments, and was significantly reduced in pathological hearts compared to healthy controls. MeRIP (immunoprecipitation of m6A-RNA) sequencing analysis uncovered that FTO targets different sets of cardiac mRNAs in the cytoplasm and nucleus of cardiomyocytes. Knocking down FTO increased nuclear retention of cardiac mRNAs, which was reversed with FTO overexpression. Immunoprecipitation experiments demonstrated that FTO directly binds to cardiac mRNAs. To determine the effect of FTO on translation of select cardiac mRNAs, we isolated the polysome fraction from the cytoplasm of AC16 cells. Interestingly, our stable isotope labeling with amino acids in cell culture (SILAC) and mass spectrometry analyses suggested increased expression of cardiac contractile proteins with FTO overexpression. Conclusion: We demonstrate that FTO positively regulates post-transcriptional nuclear export, polysome binding of cardiac contractile mRNAs, and regulates their translation under pathological stimuli. By combining experimental and predictive models in human and mice, we have characterized the transcriptome-proteome molecular interplay regulating cardiac function.
Abstract OEC103: ATP-dependent Citrate Lyase Drives Metabolic Remodeling In The Heart During Cancer
Authors: Shijie Liu, Seth Gammon, Lin Tan, Janet Pham, Philip L Lorenzi, Heinrich Taegtmeyer, David Piwnica-Worms, James F Martin, Anja Karlstaedt
Journal: Circulation Research (2022)

Cardiovascular diseases and cancer are the leading causes of death worldwide. Recurrent mutations of metabolic enzymes in cancer cells provide benefits for tumor growth, while creating a systemic metabolic phenotype and increasing the risk for adverse cardiac events. We recently showed that tumors producing the oncometabolite D-2-hydroxyglutarate increase ATP citrate lyase activity and histone acetylation in the heart. How cancer cells drive metabolic remodeling in the heart, and whether ATP citrate lyase is critical for cardiac adaptation during cancer, remains poorly understood. We co-cultured wildtype adult mouse ventricular cardiomyocytes with colorectal cancer cells overexpressing ATP citrate lyase. Co-culture of cardiomyocytes with colorectal cancer cells was associated with reduced expression of ATP citrate lyase, pyruvate dehydrogenase, and mitochondrial complex I, suggesting that the cancer cell environment impaired mitochondrial function in vitro. In vitro modulation of ATP citrate lyase activity abrogated the metabolic alterations in cultured cardiomyocytes indicating that ATP citrate lyase drives remodeling during cancer. Accordingly, we created mice lacking ATP citrate lyase in the heart using CRISPR-Cas 9 genomic knockout. Loss of ATP citrate lyase leads to left ventricular systolic dysfunction and causes global gene and protein expression changes in the heart. Targeted mass spectrometry-based metabolomics and lipidomics showed decreased acetyl-CoA and succinyl-CoA levels in isolated cardiomyocytes, while the abundance of cholesterol esters increased. In vivo [ 18 F]-FDG-positron emission tomography revealed that animals lacking ATP citrate lyase increased plasma glucose uptake compared to animals with cardiac ATP citrate lyase expression. These findings are consistent with maladaptive metabolic remodeling and impaired oxidative metabolism during heart failure. Manipulating the activity of ATP citrate lyase using BMS303141 (0.5 μM) in ex vivo perfused wildtype rat hearts caused a rapid decline in cardiac power and increased utilization of glucose confirming our in vivo mouse studies. Conversely, inhibition of ATP citrate lyase during oncometabolic stress via D-2-hydroxyglutarate improved cardiac contractile function via redirection of Krebs cycle flux and provision of ATP levels. Together these data demonstrate that ATP citrate lyase regulates oxidative metabolism and structural remodeling in the heart and creates a targetable metabolic liability during cancer.
Abstract P1126: Development Of A Tissue Engineered Small Vascular Graft With Human Amnion Membrane
Authors: Bo Wang, Xiaolong Wang
Journal: Circulation Research (2022)

The vascular transplantation is an established therapy for vascular diseases by replacing or bypassing the damaged blood vessel with a functional vascular graft. Autologous blood vessels are considered as the gold standard grafts for vascular transplantation, but the limited tissue source and the high morbidity associated with tissue harvesting have restricted their therapeutic potential. Vascular tissue engineering represents an alternative solution to replace the autologous blood vessels by developing an artificial conduit which can closely mimic the nature blood vessel. However, clinical trials with small vascular grafts are disappointing. The aim of this study is to investigate the feasibility of constructing a small vascular graft from the decellularized amniotic membrane (DAM graft) via different crosslinking methods. The human amnion membrane was decellularized, trimmed into 5 cm x 8 cm rectangular shape, and rolled around a catheter (diameter =1.2 mm) to make the primary DAM graft. Each of the resulting conduits was additionally crosslinked with: a) 0.1% glutaraldehyde; b) 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (20mM) / N-hydroxy succinimide (10mM) (EDC-NHS); c) 0.5% genipin; and d) no-crosslinking as control group. Our results demonstrated the structural integrity, material stability, mechanical behaviors, and biocompatibilities of the DAM grafts can be modified by the chemical crosslinking treatment. In which, the genipin crosslinked DAM graft exhibited the most integrated layered structure. Its level of material stability was comparable to those of the glutaraldehyde and the EDC-NHS crosslinked DAM grafts. Furthermore, the genipin crosslinking did not significantly affect the mechanical properties of the DAM graft. The genipin-crosslinked DAM graft was further tested in vivo by implanting it in a rat abdominal aorta replacement-model. All rats implanted with the genipin-crosslinked DAM graft exhibited a blood vessel patent up to 9-month post-implantation. In conclusion, we represented a potential avenue to construct a flexible vascular graft that has the patient-specific dimension and meet specific demands for biological and mechanical performance criteria by using the DAM followed by lyophilization and the genipin.
Abstract P1077: Nicotine Compromises Metabolic Adaptation Of The Heart To Injury By Altering PHLPP Isoforms
Authors: Khaja Shameem Mohammed Abdul, Cekia Wilson, Nicole Purcell
Journal: Circulation Research (2022)

Rationale: Cardiovascular (CV) disease remains the leading cause of death and disability in the US and worldwide and tobacco use is a major risk factor for increasing the incidence of disease. Consequently, there is a need for understanding the cardiovascular impact of systemic nicotine on cardiac physiology and heart failure progression following injury. We have demonstrated that removal of PH domain leucine-rich repeat protein phosphatase 1 (PHLPP1) increases Akt activity and protects the heart from oxidative damage, however downregulation of PHLPP2 causes damage. Preliminary data suggest that exposure to nicotine increases PHLPP1 and decreases PHLPP2 levels in the heart. Therefore, linking the direct pathogenic effects of nicotine on these cell-survival intracellular pathways such as those that utilize PHLPP1 activity needs to be rigorously examined for therapeutic efficacy and intervention. Hypothesis: We hypothesize that exposure to high levels of nicotine will compromise the heart and increase susceptibility to ischemic injury by altering PHLPP isoform expression. Methods: Using in vivo systems we investigated the effect of nicotine exposure on PHLPP expression and cardiomyocyte function and injury. Male and female wild-type WT (n=4) and PHLPP1 KO (n=4) mice were implanted with osmotic minipumps containing nicotine (5mg/kg/day) or saline for 7days and changes in protein and gene expression were examined. A second cohort of WT animals was exposed to nicotine (7 days) and subjected to 1 hour ischemia and 24 hours reperfusion (n=6). Results: Following 7 days of nicotine exposure, we found PHLPP1 protein expression was significantly increased (1.7 ± 0.25 fold) and PHLPP2 significantly decreased (0.8 ± 0.04 fold) in the hearts of WT mice. However, in PHLPP1 KO mice, nicotine exposure significant increased PHLPP2 levels in the heart (1.5 ± 0.044fold). Also, we found that exposure to nicotine suppressed genes important for mitochondrial biogenesis and decreased antioxidant protein expression in the hearts of WT mice while antioxidant signaling was significantly increased in KO hearts. Following 7 days of nicotine exposure WT mice have increased infarct injury (39% ± 3.2, n=6) following 24-hour reperfusion compared to saline treated WT (31% ± 0.55, n=4) with the same area at risk. Preliminary studies found that PHLPP1 KO significantly protected the heart from ischemic injury (26% ± 0.38, n=3), however the effect in the presence of nicotine is under investigation. Conclusions: Our data suggests that nicotine exposure has detrimental effects on the heart by altering PHLPP isoform expression which compromises oxidative signaling and increases injury. Further studies will investigate the mechanism of nicotine induced PHLPP isoform expression both in vitro and in vivo and determine whether targeting PHLPP1 could significantly impact cardiac outcome associated with nicotine use.
Abstract P1112: Inhibition Of Wnt Signaling Protects Against Myxomatous Valve Disease In A Mouse Model Of Marfan Syndrome
Authors: Na Xu, Katherine E Yutzey
Journal: Circulation Research (2022)

Introduction: Myxomatous valve disease (MVD) is the most common cause of mitral regurgitation, characterized by valve leaflet thickening and progressive valve degeneration, leading to impaired cardiac function and heart failure. MVD in a mouse model of Marfan syndrome (MFS) includes valve leaflet thickening and increased immune cell infiltration. However, the underlying mechanisms by which immune cells are recruited in MFS valves remain undefined. Hypothesis: Inhibition of Wnt signaling prevents immune cell recruitment and MVD progression in MFS valves. Methods: Mice with the mutation of Fibrillin 1 ( Fbn1 C1039G/+ ) recapitulate histopathological features of MFS and Wnt signaling activity was detected in TCF/Lef-lacZ reporter mice. Inhibition of Wnt signaling was achieved by conditional induction of the soluble Wnt inhibitor Dkk1 in periostin-expressing valve interstitial cells of Periostin-Cre; tetO-Dkk1; R26rtTA; TCF/Lef-lacZ; Fbn1 C1039G/+ mice. Dietary doxycycline was administered for one month beginning with MVD initiation (1-month-old) or MVD progression (2-month-old). Histological evaluation and immunofluorescence for immune cells were performed. Results: Wnt signaling as detected by TCF/Lef-reporters is activated early in mitral valve disease progression, prior to immune cell infiltration in Fbn1 C1039G/+ mice. Inhibition of Wnt signaling by Dkk1 induction at 1-month of age reduced valve leaflet thickness with decreased CD45+ leukocytes in Fbn1 C1039G/+ mice. However, later Wnt inhibition starting at 2 months did not alter valve leaflet thickness. Conclusions: Inhibition of early Wnt signaling ameliorates myxomatous valve degeneration and immune cell infiltration previously demonstrated to be required for progression of MVD.